1. Field of the Invention
The present invention relates to inhibitors for protein kinases, and more particularly, to a type-S protein kinase inhibitor having a selective inhibitory effect on a protein kinase.
2. Description of Related Art
A protein kinase plays a critical role in an organism. Because protein kinases are often over-expressed in tumor cells, the inhibitions of the protein kinases can be used to control tumor growths. Currently, several protein kinase inhibitors have entered the stage of clinical trials. These inhibitors often inhibit many other protein kinases at the same time, leading to the occurrences of many side-effects, such as cardiotoxicity, anemia, thrombocytopenia, and the like. For example, the use of Sunitinib, a drug for treating renal cell carcinoma, inhibited 259 protein kinases (˜68%) out of the 384 tested protein kinases. Therefore, the development of a highly specific protein kinase inhibitor is beneficial to the reduction of side-effects and treatment of cancers.
Currently, protein kinase inhibitors may be preliminarily classified into three major categories (including types I, II and III). The majority of the protein kinase inhibitors are type I inhibitors. A type I inhibitor mainly targets the DFG-in active conformation, and often directly competes for an ATP-binding site. Thus, the type I inhibitors lack selectivities. A type II inhibitor binds at an ATP-binding site, and an adjacent cleft created by the induction of DFG-out conformation. A type II inhibitor has an additional reaction with αC-helix and a DFG motif, such that it is relatively more selective. A type III inhibitor is a non-ATP competitive inhibitor, such that it interacts with the allosteric site of the DFG motif, adjacent to αC-helix of the active conformation. Several studies have shown the occurrences of drug-resistant mutations in the types I, II and III inhibitors. Hence, the development of a novel type-S protein kinase inhibitor may also provide a new starting point in the treatment of wild-type and drug-resistant cancers.